Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess behavior maintained by psychoactive drugs in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify drug-seeking and drug-taking behavior. Currently, studies are focusing on cocaine, methamphetamine, nicotine, and delta-9-THC (active ingredient of marijuana) using various experimental procedures, including; intravenous self-administration to assess reinforcing efficacy, radioligand binding and quantitative autoradiography to measure density of D1, D2, mu-opioid, 5-HT and DA uptake sites in several brain regions after persistent methamphetamine or cocaine self-administration, and assessment of the effectiveness of different serotonergic or dopaminergic agonists and antagonists in attenuating methamphetamine's or cocaine's reinforcing properties. In one study, possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse, were evaluated. Cocaine and GBR-12909 differentially affected dopaminergic systems and had different reinforcing and neuroadaptive effects. In other studies, we are examining effects of caffeine exposure on reinforcing and other behavioral properties of nicotine. Rats consuming caffeine in their drinking water acquired i.v. nicotine self-administration faster and reached higher levels of intake than controls. Squirrel monkeys showed increases in nicotine self-administration responding and a marked potentiation of other behavioral effects of nicotine. Finally, research in our lab has shown that rats and monkeys will emit long chains of behavior under second-order schedules to obtain highly infrequent or even single injections of drug. Currently, second-order schedules are being used to study motivational properties of stimuli associated with cocaine or methamphetamine self-administration in rats and squirrel monkeys, to try to develop an animal model of marijuana abuse in monkeys, and to assess underlying neurobiological mechanisms. Since second-order schedules are more analogous to the human drug abuse situation, the study of pharmacological and behavioral means of reducing behavior maintained using these procedures will have important implications for prevention of HIV transmission related to drug abuse.